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Journal of Drug Research and Development

ISSN 2470-1009

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Mini Review

Volume: 3.1

Breakthroughs in Computational Approaches for

Drug Discovery
Giulia Chemi and Simone Brogi*
European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of
Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Corresponding author: Simone Brogi, European Research Centre for Drug Discovery and
Development and Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via
Aldo Moro 2, 53100 Siena, Italy, Tel: +39-0577-234389; E-mail: simonebrogi1976@hotmail.com;
brogi32@unisi.it
*

In silico methodologies have become a pivotal part of the modern

drug discovery process. Since their origin, computational techniques
demonstrated to accelerate hit selection for a given drug target, and to
significantly contribute to multiple stages of drug discovery (i.e. drug
optimization) [1]. Accordingly, in silico drug design and discovery is
in a state of constant and rapid development due to: (i) progress in
the computer science which has led to the generation of powerful and
affordable supercomputers, proliferation of available online tools,
software and databases and development of more reliable algorithms; (ii)
development of new experimental procedures for the characterization of
biological targets (i.e. X-ray crystallography and NMR spectroscopy); (iii)
the greater awareness of the molecular basis of drug action.
Herein we analyzed the most relevant computer aided drug design
(CADD) breakthroughs. A variety of computational approaches with diverse
potential applications along the drug discovery process (Figure 1) will be
discussed and the last improvements of the in silico tools and methodologies
examined.

Ligand-based and Structure-based Methods in DrugDesign

Pharmacophore modeling, three-dimensional quantitative structureactivity relationships (3D-QSAR), Comparative Molecular Field
Analysis (CoMFA) and Comparative Molecular Similarity Indices
Analysis (CoMSIA) still remain the ligand-based (LB) methods of
choice for fast virtual screening (VS) procedures. They are particularly
powerful when the three-dimensional (3D) structure of the investigated
protein is unknown [2-4]. VS is routinely employed by academia and
pharmaceutical companies to identify novel chemical entities using public
(e.g. ZINC database [5]), commercial or proprietary 3D-databases, with
the possibility to screen billion of compounds in a short time, in order to
reduce drug discovery costs [6]. The large amounts of available positive
information (i.e. biological and structural data) allow the use of large
dataset of known characterized compounds also for the development of
3D-QSAR models. These are crucial information for relating the structural
and/or physicochemical properties of compounds to their activities in
order to obtain more robust statistical in silico models for predicting
activities of novel chemical entities [7]. CoMFA and CoMSIA are powerful
tools to generate 3D-QSAR models to correlate the biological activity of a
set of molecules and their 3D shape, electrostatic and hydrogen bonding
characteristics. This correlation is derived from a series of superimposed
conformations, one for each molecule in the set. The molecular fields
around each conformation are calculated and the resulting 3D models
can be used in VS protocols by using for example SYBYL-X Suite (Certara
USA, Inc., Princeton, New Jersey, NJ).

Open Access

Received date: 23 Nov 2016; Accepted date: 19

Jan 2017; Published date: 25 Jan 2017.
Citation: Chemi G, Brogi S (2017) Breakthroughs
in
Computational
Approaches
for
Drug
Discovery. J Drug Res Dev 3(1): doi http://dx.doi.
org/10.16966/2470-1009.129
Copyright: 2017 Chemi G, et al. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.

Accordingly, the expertise in the generation of QSAR models and the

development of statistical packages employing public available databases
(considering theoretical or experimental data), made possible the
realization of revised structure-relationships models. Below are reported
important examples:
(i) 3D quantitative structure-selectivity relationships (3D-QSSRs)
models [8,9]. In this approach, by means of Phase software
(Schrdinger, LLC, New York, NY), the classical 3D-QSAR was
slightly modified taking as dependent variable the selectivity
index of the compounds and not the activity toward a selected
target (Cannabinoid Receptor 2). This allows the development of
a comprehensive structure-selectivity instead of structure-activity
model. The obtained model was successfully used to rationally
design highly selective ligands for the Cannabinoid Receptor 2
[8,10];
(ii) Multi-target quantitative structure-activity relationships (mtQSARs)
models. These are useful for simultaneously estimating activities
against different biological targets using big and unrelated datasets
of compounds [11];
(iii) 3D quantitative structure-properties relationships (3D-QSPRs)
models [12]. In detail, QSPR can be clustered in various sub-fields
including quantitative structure -reactivity (QSRRs), -toxicity
(QSTRs), -chromatography (QSCRs), -biodegradability (QSBRs),
-electrochemistry (QSERs) relationships [12].
During the last decade, many scientific contributions appeared in the
literature reporting improved QSAR methodologies. These advancements
in structure-relationships models are extremely useful for rational drug
design and for predicting ligands undesirable effects such as hERG K+
channel affinity. hERG K+ channel is a well-known antitarget responsible
for cardiotoxic effects when targeted by centrally active drugs. In fact, the
interaction of small molecules with hERG K+ channel is one of the major
issues encountered by the pharmaceutical companies related to the drug
development process. In the recent years several marketed drugs including
astemizole, droperidol, terfenadine, lidolazine, sertindole, cisapride, and
chlorpromazine have been withdrawn due to their relevant activity on
hERG K+ channel. In this context, the generation of an adequate 3D-QSAR
model based on hERG K+ channel blockers can assist the rational design
of new potentially bioactive drugs devoid of hERG K+ channel affinity.
When the information of the 3D structure of the targets in complex
with ligands are known, structure-based (SB) drug design approaches
are useful for deriving SB pharmacophore models including excluded
volumes (3D space portions in which the ligand cannot be located). The
most commonly used software for generating SB pharmacophore models

Copyright: 2017 Chemi G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Open Access

Figure 1: Computer assisted drug design (CADD) pipeline.

are: e-Pharmacophores, implemented in Maestro suite (Schrdinger,

LLC, New York, NY), LigandScout (Inte: Ligand GmbH, Vienna, Austria),
Catalyst, implemented in Discovery Studio (Accelrys, Inc., San Diego,
CA, USA) and SB pharmacophore, implemented in Molecular Operating
Environment (MOE) (Chemical Computing Groups (CCG), Montreal,
QC, Canada). Among them, the e-Pharmacophores method achieves
the advantages of both ligand- and structure-based approaches by
generating energetically optimized SB pharmacophores that can be used
to rapidly screen billions of compounds. Indeed, SB models are employed
in large-scale chemical databases screening procedures. As reported
for LB methods, the progress in the experimental procedures and the
recent improvements in CPU performances coupled to the availability
of large public 3D-chemical libraries, gave a boost to this computational
approach. Intriguingly, a relevant advancement in SB pharmacophore
modeling is represented by the use of multiple SB pharmacophore models,
built employing available crystal structures of the protein of interest in
complex with diverse ligands, in VS protocols. The SB models can be used
as sequential filtering tools for screening chemical libraries. Alternatively,
they can be combined in an inclusive SB pharmacophore model taking
into account the most relevant interactions of ligands into the receptor
for generating a comprehensive SB pharmacophore [13]. In both ways,
multiple SB pharmacophore models can be used in VS or in rational
ligand design for identifying novel chemical entities or for optimizing
existing hits. Likewise, LB and SB methods can be combined for obtaining
more reliable hybrid computational protocols. Following this approach a
performance increase in retrieving active molecules for a given target has
been observed [2].

Challenges in Molecular Docking and Protein Flexibility

in Drug-Design
Regarding molecular docking techniques, important advances have
been reported in the last few years relative to the in silico methods able
to accommodate ligands into the binding site of their biological target.

Docking algorithms and scoring functions can generate structures of

receptor-ligand complexes; they may rank compounds, and can estimate
binding energies/affinities using specific algorithms. Consequently,
molecular docking is the most commonly used tool to screen large
chemical databases directly into the binding site of the selected biological
target and can be applied to a wide array of different clinically-relevant
proteins from human, parasites, viruses or other organisms. The abovementioned procedure, defined as High Throughput Docking (HTD),
to date can be applied to a wide range of different targets [14,15]. This
is possible thanks to the recent advances in computing capabilities,
molecular simulation algorithms, the growing number of available
experimental 3D protein structures, and of robust molecular models in
turn produced by using novel homology modeling techniques (i.e. models
generated by using multiple templates). Recently, molecular docking has
also been applied in a novel way to identify and validate potential targets
for active compounds (target fishing) [16]. Considering the great number
of available crystal structures, paralleled by the advantages of phenotypic
screening methodologies, HTD of bioactive compounds against relevant
targets, coupled to the evaluation of the binding free energy, could aid
the identification of an unknown target for a given bioactive compound.
Classical docking programs such as Glide (Schrdinger, LLC, New York,
NY), Autodock, Genetic Optimization for Ligand Docking (GOLD) (The
Cambridge Crystallographic Data Centre, Cambridge, UK) can be used
for target fishing procedure. Moreover an automated procedure, namely
Virtual Screening Workflow (VSW), for performing multiple docking
considering different proteins combined with the evaluation of the
binding energy of the selected ligand has been implemented in Maestro
suite (Schrdinger, LLC, New York, NY). Also, different online tools are
available for identifying potential targets for a given small molecule (i.e
SwissTargetPrediction [17]). These tools consider the similarity of the
molecule without targets with compounds known to be active against
specific ones. Despite the great improvement in amount and quality of data
available in the Protein Data Bank (PDB), in terms of number of proteins,
resolution of crystals, and in general in terms of reliability of the protein

Citation: Chemi G, Brogi S (2017) Breakthroughs in Computational Approaches for Drug Discovery. J Drug Res Dev 3(1): doi http://dx.doi.
org/10.16966/2470-1009.129

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structures, several drawbacks for target fishing have been recently reported
(i.e. improper pose predictions, scoring failures, binding site-ligand
protonation interdependence, problems associated with generation of
heterogeneous collection of binding cavities) [18]. Furthermore, modified
molecular docking simulations aimed at improving the performance of
standard molecular docking methods, continue to appear in the literature.
A technique called ensemble docking was recently developed with the
purpose of including protein flexibility in molecular docking calculation
using multiple protein conformations. Consecutive docking calculations
of each ligand into different conformations of a target receptor, represent
a valuable method to mimic the dynamic nature of the biological target.
In general, the performance of the ensemble docking technique is
superior to that reported for docking into a single receptor conformation
[19]. Another modified docking technique aimed at taking into account
the protein flexibility is the Induced Fit Docking (IFD). This latter
encompasses various steps such as ligands and proteins preparation and
molecular docking, and induces conformational changes in the binding
site to accommodate the ligand. In fact, this technique exhaustively
identifies potential binding modes and related conformational changes
by side-chain sampling, and backbone minimization in a selected radius
around the poses found during the initial docking stage of the protocol
[20]. Interestingly, a modified IFD protocol combining molecular docking
with a rule-based approach to intrinsic reactivity has been developed for
predicting potential sites of metabolism (soft spots) for a given ligand.
This technique is useful for designing optimized derivatives which bear
functionalities able to mask the identified soft spots. The IFD procedure
calculates the accessibility degree of compounds to the cytochromes
P450 (CYP) reactive center. The reactivity rules have been parametrized
in P450 Site of Metabolism Prediction software (Schrdinger, LLC, New
York, NY). The reactivity is predicted with a linear free energy approach
based on the Hammett and Taft scheme, where the reactivity of a given
atom is the sum of a baseline reactivity rate and a series of perturbations
determined by the connectivity. This procedure is very useful for designing
ligands with improved metabolic stability [21]. Further advances in
docking calculations have been recently carried out by estimating ab
initio charges of a given ligand for improving the docking predictions.
The Quantum Mechanical-Polarized Ligand Docking (QPLD) workflow,
implemented in Maestro suite (Schrdinger, LLC, New York, NY) [22],
aims at improving the partial charges assigned to the atoms of the ligand
in a docking run by replacing them with charges derived from Quantum
Mechanical (QM) calculations. The computation is performed applying
hybrid Quantum and Molecular Mechanical (QM/MM) method, where
the protein is considered as the MM region and the ligand is defined as
the QM region. In this way, the polarization of the charges on the ligand
by the receptor is taken into consideration, and re-docking of the ligand
is performed considering these QM charges. QPLD represents one of the
recent applications of the hybrid QM/MM scoring method, which has
rapidly become one of the most prevalent tools for investigating chemical
reactivity in biomolecular systems, allowing the modeling of bondformation and -disruption [23]. However, the high computational costs
for performing high-level QM calculations have restricted the applicability
of these approaches. For hits identification by docking techniques, many
improvements have been done about the scoring functions on the basis of
entropy, desolvation effects, and target specificity.

Enhanced-Sampling Molecular Dynamics approaches

and Coarse-grained Molecular Dynamics in Drug Design
To investigate ligand-receptor complexes and in general the dynamics
and thermodynamics of biological systems, Molecular Dynamics (MD)
simulations represent one of the major computational resources, since
their introduction in the late 70s [24,25]. MD procedure calculates the
behavior of a molecular system in a considered time, providing extensive

Open Access
data on fluctuations and conformational changes of proteins and nucleic
acids [26]. At the moment, several programs for performing MD
simulation are available. Among them, ACEMD (Accelera Ltd, London,
UK), Chemistry at Harvard Macromolecular Mechanics (CHARMM),
Assisted Model Building with Energy Refinement (AMBER) (University
of California, San Francisco, CA), Groningen Machine for Chemical
Simulations (GROMACS), Nanoscale Molecular Dynamics (NAMD)
(Theoretical and Computational Biophysics group, University of Illinois
at Urbana-Champaign, Urbana, IL) and Desmond (D. E. Shaw Research,
New York, NY), are the most popular. Currently, it is possible to simulate
complex systems (whole proteins) in solution with an explicit solvent,
membrane embedded proteins, or large macromolecular complexes
like nucleosomes or ribosomes [27-29]. The improvement of the latter
technique, in terms of the size of the investigated molecular systems as
well as in terms of extent of the performed simulations (i.e. s and/or
ms of simulations) [30,31] is in large part a consequence of the use of
high performance computing, parallelized computer architectures, and
the accessibility to more efficient algorithms. The improvement of MD
simulations is also linked to the development of more accurate force fields,
able to evaluate in a detailed manner the system under investigation in
order to reproduce the properties of every particle of that system [32,33].
Recent examples are the improvement of CHARMM, AutoDock4Zn and
Optimized Potential for Liquid Simulations (OPLS) force fields. These
advances mainly concern: (i) the improved accuracy in generating
polypeptide backbone conformational ensembles for intrinsically
disordered peptides and proteins (CHARMM) [34]; (ii) the inclusion
of specialized potential describing the interactions of zinc-coordinating
ligands, describing both the energetic and geometric components of the
interaction (AutoDock4Zn) [35]; (iii) the addition of off-atom charge sites
for representing halogen bonding and aryl nitrogen lone pairs and the
complete refit of peptide dihedral parameters to better model the native
structure of proteins (OPLS) [36]. The progresses in the development
of more accurate force fields made possible a more accurate prediction
of the binding free energy. This latter is extremely useful in the lead
optimization step [37,38]. Despite the advances in MD simulations, the
excessive computational cost in terms of time computing, very often
discouraged scientists to run adequate number of replicas to assess the
reproducibility of the approach. For bypassing the time-scale restrictions
of conventional MD simulations, new hardware resources have been
developed. Accordingly, MD simulations are currently performed by
graphics-processing-units (GPUs), increasing the rate of calculation of an
order of magnitude. Moreover, new processors for these MD simulations
have been specifically designed, building supercomputers able to
accomplish microseconds of simulation per day [39]. The lust to perform
long simulations, within a realistic time, inspired the development of a
variety of enhanced sampling practices, employing constraints to speed
up the progression of a system. For instance, there are several methods
such as metadynamics [40], accelerated MD [41], and Coarse-Grained
MD (CGMD) [42] that alter the normal progression of the system with
a history-dependent biasing potential along the trajectory followed by a
properly selected set of collective variables. In CGMD the accessible timescales of MD simulations are increased and the actual degrees of freedom
of the system are reduced by linking atoms into aggregate particles.
Although this technique has proven useful to study biomolecular systems,
it is plagued by reduced resolution since could not succeed in capturing
subtle but relevant properties such as the H-bonds system in solvents. MD
simulations can treat proteins and ligands in a flexible manner, allowing
the relaxation of the binding site around the ligand considering the effect of
explicit water molecules. More accurate MD-based methods are available
for estimating the binding free energy (thermodynamic integration (TI),
linear interaction energy (LIE), free energy perturbation (FEP), and
molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA)). As

Citation: Chemi G, Brogi S (2017) Breakthroughs in Computational Approaches for Drug Discovery. J Drug Res Dev 3(1): doi http://dx.doi.
org/10.16966/2470-1009.129

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above-mentioned, the accuracy in the estimation of the binding free energy

using MD simulations can increase the efficiency of the drug discovery
process [43,44]. A great improvement of the MD technique is represented
by High Throughput Molecular Dynamics (HTMD), a novel technique
based on the simulation throughput which allows understanding of drug
interaction with biological targets with a high degree of resolution and
accuracy. The method is a massive-scale MD simulation and can be used
to screen chemical databases. This method showed, in the hit discovery
step, higher performances than the HTD [45].

Conclusion
In summary, the huge technological progresses in hardware and software
resources, algorithms design as well as the advances in the development
of new experimental procedures for characterizing biological targets,
make computer-assisted approaches (combined with specific biological
investigations) the most valuable methods for limiting the time and costs
of pre-clinical research. Furthermore, CADD approaches are employed
for reducing the use of animals for in vivo testing, for helping the design
of more effective and safer drugs and for contributing to the repositioning
of known drugs. CADD represents a key instrument to assist medicinal
chemists in drug design, discovery, development, and hit-optimization
steps during the drug discovery process.

Acknowledgements
The authors wish to thank the European Research Centre for Drug
Discovery and Development (NatSynDrugs) for the support. We are also
grateful to Prof. Giuseppe Campiani, Prof. Stefania Butini, Prof. Sandra
Gemma and Dr. Margherita Brindisi for their fruitful discussion during
the elaboration of this manuscript. The British Society of Antimicrobial
Chemotherapy (BSAC) is kindly acknowledged (grant number
GA2016_087R to SB).

Conflict of Interest
The authors declare no competing financial interest concerning the
publication of this paper.

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Citation: Chemi G, Brogi S (2017) Breakthroughs in Computational Approaches for Drug Discovery. J Drug Res Dev 3(1): doi http://dx.doi.
org/10.16966/2470-1009.129